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Author

Miki Fujimura

Other affiliations: Stanford University
Bio: Miki Fujimura is an academic researcher from Tohoku University. The author has contributed to research in topics: Moyamoya disease & Cerebral blood flow. The author has an hindex of 50, co-authored 289 publications receiving 11341 citations. Previous affiliations of Miki Fujimura include Stanford University.


Papers
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Journal ArticleDOI
TL;DR: It is shown that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication, and suggested that AQP4 inhibition may provide a new therapeutic option for reducingbrain edema in a wide variety of cerebral disorders.
Abstract: Cerebral edema contributes significantly to morbidity and death associated with many common neurological disorders. However, current treatment options are limited to hyperosmolar agents and surgical decompression, therapies introduced more than 70 years ago. Here we show that mice deficient in aquaporin-4 (AQP4), a glial membrane water channel, have much better survival than wild-type mice in a model of brain edema caused by acute water intoxication. Brain tissue water content and swelling of pericapillary astrocytic foot processes in AQP4-deficient mice were significantly reduced. In another model of brain edema, focal ischemic stroke produced by middle cerebral artery occlusion, AQP4-deficient mice had improved neurological outcome. Cerebral edema, as measured by percentage of hemispheric enlargement at 24 h, was decreased by 35% in AQP4-deficient mice. These results implicate a key role for AQP4 in modulating brain water transport, and suggest that AQP4 inhibition may provide a new therapeutic option for reducing brain edema in a wide variety of cerebral disorders.

1,418 citations

Journal ArticleDOI
TL;DR: Results indicate that RNF213 is the first identified susceptibility gene for MMD, and it is confirmed that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts.
Abstract: Moyamoya disease (MMD) shows progressive cerebral angiopathy characterized by bilateral internal carotid artery stenosis and abnormal collateral vessels. Although ∼ 15% of MMD cases are familial, the MMD gene(s) remain unknown. A genome-wide association study of 785,720 single-nucleotide polymorphisms (SNPs) was performed, comparing 72 Japanese MMD patients with 45 Japanese controls and resulting in a strong association of chromosome 17q25-ter with MMD risk. This result was further confirmed by a locus-specific association study using 335 SNPs in the 17q25-ter region. A single haplotype consisting of seven SNPs at the RNF213 locus was tightly associated with MMD (P = 5.3 × 10(-10)). RNF213 encodes a really interesting new gene finger protein with an AAA ATPase domain and is abundantly expressed in spleen and leukocytes. An RNA in situ hybridization analysis of mouse tissues indicated that mature lymphocytes express higher levels of Rnf213 mRNA than their immature counterparts. Mutational analysis of RNF213 revealed a founder mutation, p.R4859K, in 95% of MMD families, 73% of non-familial MMD cases and 1.4% of controls; this mutation greatly increases the risk of MMD (P = 1.2 × 10(-43), odds ratio = 190.8, 95% confidence interval = 71.7-507.9). Three additional missense mutations were identified in the p.R4859K-negative patients. These results indicate that RNF213 is the first identified susceptibility gene for MMD.

536 citations

Journal ArticleDOI
01 May 2014-Stroke
TL;DR: Although statistically marginal, Kaplan–Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding.
Abstract: Background and purpose About one half of those who develop adult-onset moyamoya disease experience intracranial hemorrhage. Despite the extremely high frequency of rebleeding attacks and poor prognosis, measures to prevent rebleeding have not been established. The purpose of this study is to determine whether extracranial-intracranial bypass can reduce incidence of rebleeding and improve patient prognosis. Methods This study was a multicentered, prospective, randomized, controlled trial conducted by 22 institutes in Japan. Adult patients with moyamoya disease who had experienced intracranial hemorrhage within the preceding year were given either conservative care or bilateral extracranial-intracranial direct bypass and were observed for 5 years. Primary and secondary end points were defined as all adverse events and rebleeding attacks, respectively. Results Eighty patients were enrolled (surgical, 42; nonsurgical, 38). Adverse events causing significant morbidity were observed in 6 patients in the surgical group (14.3%) and 13 patients in the nonsurgical group (34.2%). Kaplan-Meier survival analysis revealed significant differences between the 2 groups (3.2%/y versus 8.2%/y; P=0.048). The hazard ratio of the surgical group calculated by Cox regression analysis was 0.391 (95% confidence interval, 0.148-1.029). Rebleeding attacks were observed in 5 patients in the surgical group (11.9%) and 12 in the nonsurgical group (31.6%), significantly different in the Kaplan-Meier survival analysis (2.7%/y versus 7.6%/y; P=0.042). The hazard ratio of the surgical group was 0.355 (95% confidence interval, 0.125-1.009). Conclusions Although statistically marginal, Kaplan-Meier analysis revealed the significant difference between surgical and nonsurgical group, suggesting the preventive effect of direct bypass against rebleeding. Clinical trial registration url http://www.umin.ac.jp/ctr/index.htm. Unique identifier: C000000166.

484 citations

Journal ArticleDOI
TL;DR: The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that M MP-9 may play an active role in early vasogenic edema development after stroke.
Abstract: During cerebral ischemia blood-brain barrier (BBB) disruption is a critical event leading to vasogenic edema and secondary brain injury. Gelatinases A and B are matrix metalloproteinases (MMP) able to open the BBB. The current study analyzes by zymography the early gelatinases expression and activation during permanent ischemia in mice (n = 15). ProMMP-9 expression was significantly (P < 0.001) increased in ischemic regions compared with corresponding contralateral regions after 2 hours of ischemia (mean 694.7 arbitrary units [AU], SD ± 238.4 versus mean 107.6 AU, SD ± 15.6) and remained elevated until 24 hours (mean 745.7 AU, SD ± 157.4). Moreover, activated MMP-9 was observed 4 hours after the initiation of ischemia. At the same time as the appearance of activated MMP-9, we detected by the Evan's blue extravasation method a clear increase of BBB permeability. Tissue inhibitor of metalloproteinase-1 was not modified during permanent ischemia at any time. The ProMMP-2 was significantly (P < 0.05) increased only after 24 hours of permanent ischemia (mean 213.2 AU, SD ± 60.6 versus mean 94.6 AU, SD ± 13.3), and no activated form was observed. The appearance of activated MMP-9 after 4 hours of ischemia in correlation with BBB permeability alterations suggests that MMP-9 may play an active role in early vasogenic edema development after stroke.

410 citations

Journal ArticleDOI
01 Jan 2008-Stroke
TL;DR: The estimated prevalence of moyamoya disease in Japan has almost doubled during the recent decade and the clinicoepidemiological features of the patients in the present study were almost similar to those obtained in previous ones.
Abstract: Background and Purpose— The objectives of the present study were to estimate an annual number of patients with moyamoya disease in Japan and to describe the clinicoepidemiological features of the disease. Methods— The study consisted of 2 questionnaire surveys, which were distributed to randomly selected departments of neurosurgery, internal medicine, neurology, cerebrovascular medicine, and pediatrics in hospitals throughout Japan. The first survey inquired about the number of the patients treated in 2003, and the second requested additional detailed clinicoepidemiological information about each patient identified in the first survey. Results— In 2003, the total number of patients treated in Japan was estimated at 7700 (95% confidence interval, 6300 to 9300). Sex ratio (women to men) of the patients was 1.8. For men, the peak of moyamoya disease was observed in patients aged 10 to 14 years and for women aged 20 to 24 years. Annual rate of newly diagnosed cases in 2003 was 0.54 per 100 000 population. Fam...

380 citations


Cited by
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Journal ArticleDOI
TL;DR: Astrocyte functions in healthy CNS, mechanisms and functions of reactive astrogliosis and glial scar formation, and ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions are reviewed.
Abstract: Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions.

4,075 citations

Journal ArticleDOI
TL;DR: This article provides a framework that can be used to generate testable hypotheses and treatment strategies that are linked to the appearance of specific pathophysiological events within the ischaemic brain.

3,785 citations

Journal ArticleDOI
TL;DR: A major unifying thread of the review is a consideration of how the changes occurring during and after ischemia conspire to produce damaging levels of free radicals and peroxynitrite to activate calpain and other Ca(2+)-driven processes that are damaging, and to initiate the apoptotic process.
Abstract: This review is directed at understanding how neuronal death occurs in two distinct insults, global ischemia and focal ischemia. These are the two principal rodent models for human disease. Cell dea...

2,960 citations

Journal ArticleDOI
TL;DR: It is shown that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier, which may represent the first example of a novel class of autoimmune channelopathy.
Abstract: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that selectively affects optic nerves and spinal cord. It is considered a severe variant of multiple sclerosis (MS), and frequently is misdiagnosed as MS, but prognosis and optimal treatments differ. A serum immunoglobulin G autoantibody (NMO-IgG) serves as a specific marker for NMO. Here we show that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier. NMO may represent the first example of a novel class of autoimmune channelopathy.

2,024 citations

Journal ArticleDOI
TL;DR: This new research focus addresses an important need in stroke research, provides challenges and opportunities that can be used to therapeutic advantage and is focused on how blood vessels and brain cells communicate with each other.
Abstract: Over the past two decades, research has heavily emphasized basic mechanisms that irreversibly damage brain cells after stroke. Much attention has focused on what makes neurons die easily and what strategies render neurons resistant to ischaemic injury. In the past few years, clinical experience with clot-lysing drugs has confirmed expectations that early reperfusion improves clinical outcome. With recent research emphasizing ways to reduce tissue damage by both vascular and cell-based mechanisms, the spotlight is now shifting towards the study of how blood vessels and brain cells communicate with each other. This new research focus addresses an important need in stroke research, and provides challenges and opportunities that can be used to therapeutic advantage.

1,577 citations